Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E–Knockout Mice

Park, Tae‐Sik; Panek, Robert L.; Mueller, Sandra Bak; Hanselman, Jeffrey C.; Rosebury, Wendy S.; Robertson, Andrew W.; Kindt, Erick; Homan, Reynold; Karathanasis, Sotirios K.; Rekhter, Mark D.

doi:10.1161/01.cir.0000148370.60535.22

Cited by 204 publications

(166 citation statements)

References 31 publications

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“…Indeed, intraperitoneal injection of myriocin did not change mouse plasma cholesterol levels on the chow or high fat diets (Tables I and III). In a most recent report, Park et al showed that oral myriocin administration causes significant reduction of plassma cholesterol and SM levels, thus causing a dramatic reduction of atherosclerotic lesions in apoE KO mice on a high cholesterol diet (21). The different outcome of that study and ours, in terms of plasma cholesterol levels, might be due to the different methods of myriocin delivery.…”

Section: Discussionmentioning

confidence: 58%

Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice

Hojjati

Zhou

et al. 2005

Journal of Biological Chemistry

263

211

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Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, all of which may well have an impact on the development of atherosclerosis. To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized myriocin to inhibit mouse serine palmitoyl-CoA transferase (SPT), the key enzyme for sphingolipid biosynthesis. We injected 8-week-old apoE-deficient mice with myriocin (0.3 mg/ kg/every other day, intraperitoneal) for 60 days. On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001). Plasma total cholesterol and triglyceride levels demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (42% in root and 36% in en face assays) (p < 0.01). On a high fat diet, myriocin treatment caused marked decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (59, 66, and 81%, respectively) (p < 0.0001), and a marked increase in plasma phosphatidylcholine levels (100%) (p < 0.0001). Total cholesterol and triglyceride demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (39% in root and 37% in en face assays) (p < 0.01). These results indicate that, apart from cholesterol levels, sphingolipids have an effect on atherosclerotic development and that SPT has proatherogenic properties. Thus, inhibition of SPT activity could be an alternative treatment for atherosclerosis.Sphingolipids have many biological functions, including cell membrane formation, signal transduction, and lipid metabolism, and all of these may be related to the development of atherosclerosis. Serine palmitoyl-CoA transferase (SPT) 1 is the rate-limiting enzyme in the biosynthesis of sphingolipids (1). It has long been known that SPT plays an important role in the metabolism of sphingolipids, but its role in other lipid metabolisms and atherosclerosis has not been unequivocally determined. When SPT activity is increased in rat liver (2) and lung (3), sphingolipid formation is likewise increased. The activity of SPT is heightened in the aortas of rabbits fed a high cholesterol diet (4). Two candidate cDNAs for yeast SPT, termed LCB1 and LCB2, have been cloned (5, 6), and the translated sequences indicate that their gene products have a 21% amino acid sequence identity (6). The lack of SPT activity in a yeast strain defective in LCB1 or LCB2, together with the protein similarity data, suggest that the two genes encode subunits of SPT (6). Mouse and human LCB1 and LCB2 cDNA homologues have also been cloned (7,8). In mouse, the two mRNAs have the same tissue distribution (lung, kidney Ͼ brain Ͼ cartilage, skin Ͼ heart Ͼ liver Ͼ muscle), and the ratio of the amounts of the two transcri...

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Section: Discussionmentioning

confidence: 58%

Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice

Hojjati

Zhou

et al. 2005

Journal of Biological Chemistry

263

211

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“…Park et al have shown that giving myriocin significantly decreased the levels of sphingomyelin in a dose dependent manner. Furthermore, they were able to show that myriocin also lowered total cholesterol, triglycerides, VLDL and LDL [82,83]. This is not very surprising, though, as myriocin has been found to cause suppression of HMG CoA reductase.…”

Section: Ceramide and Potential Therapeuticsmentioning

confidence: 83%

Ceramide: A common pathway for atherosclerosis?

et al. 2008

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Plasma sphingomyelin concentration is correlated with the development of atherosclerosis. It has been found to exist in significantly higher concentrations in aortic plaque. This appears to have clinical relevance as well as it has been shown to be an independent predictor of coronary artery disease. Ceramide, the backbone of sphingolipids, is the key component which affects atherosclerotic changes through its important second-messenger role. This paper sheds light on some of the current literature supporting the significance of ceramide with respect to its interactions with lipids, inflammatory cytokines, homocysteine and matrix metalloproteinases. Furthermore, the potential therapeutic implications of modulating ceramide concentrations are also discussed.

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“…However, it is very unlikely that SM plays such a role, for the following reasons. i) HDL-like LpA1 containing SM may be even more effective at effluxing cholesterol from fibroblasts than LpA1 without SM (33). ii) There is evidence from animal experiments that excess SM induces an increase of VLDL-CH and LDL-CH but a decrease of HDL-CH (33,34).…”

Section: Discussionmentioning

confidence: 99%

Beyond HDL-cholesterol increase: phospholipid enrichment and shift from HDL3 to HDL2 in alcohol consumers

Schäfer

Parlesak

Eckoldt

et al. 2007

Journal of Lipid Research

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The reduction of cardiovascular mortality associated with moderate alcohol consumption is chiefly thought to be mediated by an increase of high density lipoprotein cholesterol (HDL-CH). This study highlights additional qualitative changes of HDL that might augment this antiatherogenic effect. In 279 healthy men, alcohol and nutrient consumption were evaluated. Groups 1 (n 5 62), 2 (n 5 172), and 3 (n 5 45) comprised subjects with alcohol consumption of 0-5.0, 5.1-30.0, and 30.1-75 g/day, respectively. Lipid analysis was performed in nonfractionated and fractionated plasma, including subfractions HDL 2a , HDL 2b , and HDL 3 . No difference in LDL-cholesterol was observed. Compared with group 1, groups 2 and 3 exhibited significant increases of HDL-CH (group 1, 44 6 10 mg/dl; group 2, 51 6 11 mg/dl; group 3, 55 6 11 mg/dl; mean 6 SD, P , 0.0005), accompanied by enhanced lipidation of HDL (increase of the HDL 2 -CH/HDL 3 -CH ratio). Moreover, phospholipid enrichment of HDL occurred in alcohol consumers, whereas the ratios between other HDL components remained constant. Multivariate analysis revealed alcohol to have the foremost statistical influence on changes of the HDL fraction, followed by body mass index and physical activity level. The increased lipidation of HDL found in alcohol consumers might augment the antiatherogenic effect of HDL-CH increase. In addition, the phospholipid enrichment of HDL might reduce the inflammatory response of

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Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E–Knockout Mice

Cited by 204 publications

References 31 publications

Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice

Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice

Ceramide: A common pathway for atherosclerosis?

Beyond HDL-cholesterol increase: phospholipid enrichment and shift from HDL3 to HDL2 in alcohol consumers

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